Certain n-(o-nitrophenyl and o-nitropyridyl)triazoles



United States Patent O 3,489,761 CERTAIN N-(o-NITROPHENYL AND o-NITRO-PYRIDYL)TRIAZOLES James C. Kauer, Wilmington, Del., assignor to E. I. du

Pont de Nemours and Company, Wilmington, Del., a

corporation of Delaware No Drawing. Filed Mar. 6, 1967, Ser. No. 620,666Int. Cl. C07d 55/06; A61k 27/00 US. Cl. 260-296 4 Claims ABSTRACT OF THEDISCLOSURE Novel N-(o-nitrophenylor o-nitropyridyl) triazoles useful asoral antifertility agents for male rats.

FIELD OF THE INVENTION This invention relates to novelN-(o-nitroaromatic)triazoles.

DETAILS OF THE INVENTION Although many derivatives of heterocycliccompounds have been made and used in antifungal or similar biologicalapplications, it has now been found that selected new heterocycles haveutility as male antifertility agents.

The compounds of the invention have the formula:

wherein R and R alike or different, are selected from the groupconsisting of hydrogen, halogen and lower alkyl, carbacyl having up to 5carbon atoms and benzoyl, and aryl, aralkyl, alkaryl and haloaryl havingup to 7 carbons; and

A is o-nitrophenyl or o-nitropyridyl or a monohalo substitution productof o-nitrophenyl or o-nitropyridyl. The compounds where one or both of Rand R are hydrogen are preferred.

The compounds can be made by arylation of a 1,2,4 triazole havinghydrogen on nuclear nitrogen With an ortho-nitrohalobenzene or apyridine having nitro and halo groups on adjacent carbons according tothe equations:

. t In reaction (2), isomerization (tautomer1zat1on) of the initialtriazole to the corresponding 1H-1,3,4-triazole (al- 3,489,761 PatentedJan. 13, 1970 ternatively named as 4H-1,2,4-triazole) gives some of thecorresponding 1- 3 -nitro-2'-pyridyl) -1,3 ,4-triazole.

The above-defined products are new. Although in some instances closelyrelated analogs and even isomers have been previously obtained, the newcompounds differ from these prior compounds in the presence of amono-nitro group in the ortho position of the 6-membered aromatic ringcoupled with the bonding of the aromatic ring to nuclear nitrogen of theS-membered heterocyclic portion. The heterocycle has conjugatedunsaturation and 3 nitrogen atoms in the ring.

A peculiar and unexpected property of the new compounds of thisinvention as compared to previously obtained nitroaryl-substitutedheterocycles of this general class is that they inhibit sperm productionin the male rat without inhibition of male sex characterstics. Forexample, three weeks after a single dose the character of thesperm-producing and maturing tubules of a male rat is altered withoutaltering the androgen production by the tests as determined by theappearance of the ventral prostate and seminal vesicles. Thus thespecific effect as a male anti-fertility agent in male rats does notinhibit endocrine function with undesirable hormonal side efiects as arecustomarily obtained When steroidal compounds are administered.

EMBODIMENTS OF THE INVENTION The following examples further illustratethe new compounds of this invention and their preparation. In theexamples, temperatures are given in degrees centigrade and pressures areatmospheric.

-In the examples, isomer mixtures are produced in some instances. Theindividual compounds can be separated by conventional means, includjngdistillation, recrystallization or chromatography.

EXAMPLE 1 1-(o-nitrophenyl-1,2,4-triazole R and R =H andA=o-nitrophenyl) F NCH NCH n II zc a n t M N W5 1 N N H A mixture of 6.9g. of 1,2,4-triazole, 14.1 g. of ofiuoronitrobenzene, 45 ml. ofN,N-dimethylformamide and 10.6 g. of sodium carbonate was stirred andheated at reflux overnight. The product was poured on ice, and the tancrystalline product was separated by filtration. The damp solid wasrecrystallized from ml. of hot ethanol. The resulting light yellowcrystals Weighed 13.3 g. after washing with cold ethanol and ether.Recrystallization from benzene yielded colorless platelets melting at113-114,

Analysis.-Calcd. for C H N O C, 50.53; H, 3.18; N, 29.47. Found: C,51.17, 51.24; H, 3.42, 3.31; N, 29.53. The compound exhibited infraredabsorption peaks at 3110, 1620, 1600, 1545, 1505, 1428, 1363, 1308,1280,

852, 784, 750, 714, 707 and 678 crn.

In place of 1,2,4-triazole in the preceding Example 1,

the following substituted triazoles can be used to give new triazoles asshown by the following:

3-ethyl-l,2,4-triazole 3benzyl-l,2,4-triazole 3-bromo-1,2,4trlazole3-ehloro-1,2,4-triazo1e 3-propionyl-l,2,4-triazol3-pivaloyl-l,2,4-triazole 1-(o-m'trophenyl)3(and5)-(p-chlorophenyl)-1,2,4-triazole.

l-(o-nitrophenylyb (and 5)-ethyl-l,2,4-triazole.

-. 1-(o-nitrophenyl)-3(and 5)beuzyl-1,2,4-triazole.1-(o-nitrophenyl)-3(and 5)-bromo-1,2,4-trizaole. 1-(o-nitrophenyl)-3(and5)-chloro-1,2,4triazola. 1-(o-nitropheny1)-3(and 5)-propiony1-1,2,ttriazole.

. 1-(o-nitrophenyl)-3(and 5)-pivaloyl-1,2,4-triazole.

A solution of 15.9 g. of 2-chloro-3-nitropyridine and 6.9 g. of1,2,4-triazole in 50 ml. of N,N-dimethylformamide was stirred with 12 g.of anhydrous sodium carbonate and heated to 85 for 2 hours. Theresulting mixture was poured on ice, and the solid (15.3 g.) wasseparated by filtration and washed with water. After successiverecrystallization from hexane and from benzene, the1-(3'-nitro-2-pyridyl)-1,2,4-triazole melted at 136.8-138.

Analysis.-Calcd. for C H N O C, 43.98; H, 2.64; N, 36.64. Found: C,43.95; H, 2.71; N, 36.90.

When the 6-member aromatic ring is pyridyl instead of benzenoid, isomersand halogenated products are produced as shown in Table 11.

TABLE II Compound Source EtOl-I max.

Analysis.-Calcd. for C H CIN O C, 42.78; H, 2.25; N, 24.95. Found: C,42.47; H, 2.01; N, 24.51.

EXAMPLE 3 1- (3'-nitro-2'-pyridyl) -l ,2,4-triazole (R and R'H andA=3'-nitr0-2'-pyridyl) u IQ N02 M2003 g ll no \N/ 01 DNIF N Forbiological activity as described in this invention, at least one nuclearcarbon of the 5membered heterocyclic moiety should be unsubstituted,i.e., should carry hydrogen, and the 6-membered aromatic, i.e.,benzenoid or pyridyl, should have no more than one substituent inaddition to the o-nitro group.

As noted above, the compounds of this invention are, surprisingly, goodantifertility agents for male rats. The compound of the examples weretested for anti-testis activity by giving intact adult male rats asingle oral dose of compound suspended in aqueous vehicle in a volume of1.0 ml. per g. of body weight. Control rats received vehicle only. Threeweeks after treatment the rats were weighed and necropsied. Theepididymides, testes, ventral prostate and sometimes the seminalvesicles were examined for evidence of gross changes.

Testis weight decrease and/or gross changes in the serniniferous tubulesor epididymal ducts indicate an anti-fertility efi'ect. From experience,it is believed that a testis weight decrease of 50% indicates maximalactivity.) Decrease in size of ventral prostate and seminal vesiclesindicates a decrease in androgen production by the non-seminiferousportion of the testis. An ideal male anti-fertility agent would inhibitsperm production or maturation only, without any effect on testisandrogen production.

The compounds of this invention caused a dose-related decrease in testisweight compared to the testes of control rats. There were gross changesin the seminiferous tubules and epididymal ducts, but no changes wereobserved in the ventral prostate and seminal vesicles. Specificinformation is given in the following Table III, the first threecompounds of which are included in the scope of the present inventionbut the last (inactive or undesirable) two of which are not:

and aryl, aralkyl, alkaryl and haloaryl having up to 7 carbons; and

TABLE TIL-ANTI-TESTIS ACTIVITY OF COMPOUNDS OF THIS INVENTION VERSUSOTHER SELECTED COMPOUNDS Percent Change l in decrease in Epldid- Dose,testis ymal Ventral Compound Example mgJkg. weight ducts prostatel-(o-Nitrophenyl)-1,2,4-triazole 1 100 42 2. 0. 01-(o-Nitro-p-chlorophenyl)-1,2,4-triazo1e 2 150 50 2. 0 0. 0 1--mtro-2-pyridyl)-l,2,4 triazole 3 150 49 1. 8 0. 0l-(o-Nitrophenyl)1,2,3-triaz0le 50 0.33 0. 0

l50-Al1 rats died. l-(p-Nitrophenyl)-l,2,4triazo1e 150 3 0, 0

1 On a rating Scale 01 2.0=grossly abnormal, l.0=somewhat abnormal,0.0=norrnal.

In addition to the use of the compounds as anti-fertility agents forcontrol of animal populations, e.g., rodents, they can be employed aspre-emergence herbicides. For example, at an application rate of 16pounds per acre the compounds of the preceding examples exhibit toxicityto plants, particularly to mustard and marigold. The compounds of theexamples have also been found to inhibit the feeding of army worms whenapplied to their foodstuffs at up to about a 1% concentration.

Since obvious modifications and equivalents in the invention will beevident to those skilled in the chemical arts, I propose to be boundsolely by the appended claims.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A compound of the formula wherein R and R, alike or different, areselected from the group consisting of hydrogen, halogen and lower alkyl,carbacyl having up to 5 carbon atoms and benzoyl References Cited UNITEDSTATES PATENTS 2,800,486 7/1957 Grundmann et al. 260-308 OTHERREFERENCES Ainsworth et al., Journal of Medicinal and PharmaceuticalChemistry, vol. 5 pp. 383-89 (1962), RS 1 J 5.

HENRY R. J ILES, Primary Examiner A. L. ROTMAN, Assistant Examiner US.Cl. X.R.

